Publications by authors named "Vanessa Smith"

214 Publications

The burden of systemic sclerosis in Switzerland - the Swiss systemic sclerosis EUSTAR cohort.

Swiss Med Wkly 2021 07 14;151:w20528. Epub 2021 Jul 14.

Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland.

Objectives: Characteristics of Swiss patients with systemic sclerosis have not been described so far. The aim of the current study was to identify unmet needs in comparison with other European countries that could inform specific interventions to improve the care of systemic sclerosis patients.

Methods: We analysed Swiss and other European systemic sclerosis patients registered in European Scleroderma Trials And Research (EUSTAR) and the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) cohort. Demographics, clinical profiles, organ involvement and survival of established, early/mild and very early / very mild systemic sclerosis patients were described and compared between the cohorts.

Results: We included 679 Swiss and 8793 European systemic sclerosis patients in the analysis. Over 95% of patients in both cohorts were Caucasian, disease subsets were similar, and no age difference was found. The Swiss cohort had more male patients (25% vs 16% European, p = 0.005) and higher prevalence of early/mild and very early / very mild patients (26.1 vs 8.5% European and 14.9% vs 6.7% European, respectively, both p <0.0001). Disease duration in established systemic sclerosis patients at first presentation was numerically shorter but not significant in the Swiss cohort: 5.0 years (1–12) Swiss vs 6.0 years (2–12) years European, p = 0.055). Despite the earlier referral of Swiss patients to systemic sclerosis expert centres, they showed evidence of more severe disease, particularly in the limited cutaneous systemic sclerosis subset, but no differences in overall survival on longitudinal follow-up were observed.

Conclusion: This is the first report of the national Swiss EUSTAR cohort. It identifies earlier referral to systemic sclerosis expert centres, before major organ damage occurs, and when outcome can still be modified, as a priority to improve care of patients with systemic sclerosis.
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http://dx.doi.org/10.4414/smw.2021.20528DOI Listing
July 2021

Influence of Seasonal Vitamin D Changes on Clinical Manifestations of Rheumatoid Arthritis and Systemic Sclerosis.

Front Immunol 2021 29;12:683665. Epub 2021 Jun 29.

Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties (DIMI), University of Genova, IRCCS San Martino Polyclinic, Genova, Italy.

Vitamin D [1,25(OH)D-calcitriol] is basically a steroid hormone with pleiotropic biologic effects, and its impact on the regulation of immune system may influence several clinical conditions. Calcidiol (25OHD), as precursor of calcitriol, derives, for the most part (80%), from cutaneous cholesterol (7-dehydrocholesterol) under the action of UV-B (sunlight). Consequently, serum concentrations fluctuate during the year following the circannual rhythm of sun exposition. We will update about the available evidence regarding the complex influence of seasonal vitamin D changes on two different chronic connective tissue diseases, namely rheumatoid arthritis (RA) and systemic sclerosis (SSc). Notably, RA is an emblematic model of autoimmune disease with prevalent joint inflammatory features, while SSc is mainly an autoimmune progressive pro-fibrotic disease. However, in both conditions, low serum concentrations of 25OHD are involved in the pathogenesis of the diseases, and emerging data report their impact on clinical manifestations.
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http://dx.doi.org/10.3389/fimmu.2021.683665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276051PMC
June 2021

Laser speckle contrast analysis is a reliable measure of digital blood perfusion in Black Africans with systemic sclerosis.

Clin Exp Rheumatol 2021 Jul 7. Epub 2021 Jul 7.

Department of Internal Medicine, Ghent University; Department of Rheumatology, Ghent University Hospital; Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Centre (IRC), Ghent, Belgium.

Objectives: Laser speckle contrast analysis (LASCA) is evolving as a promising non-invasive tool to assess cutaneous microvascular function in systemic sclerosis (SSc). Reliability studies have mainly focused on Caucasian populations. To determine for the first time the inter-rater reliability of fingertip blood perfusion (BP) using LASCA in Black South African patients with SSc.

Methods: Consecutive Black adult patients with SSc were evaluated for peripheral BP using LASCA. Mean BP in defined regions of interest for dorsal fingertips and volar fingertips were measured in two subgroups of 20 SSc patients, each by three independent operators. Two operators were experienced in the use of the LASCA instrument and one was newly trained. Standardised protocols for conditions were followed for all measurements. Inter-rater reliability was tested using the intraclass correlation coefficient (ICC).

Results: The majority (87.5%) of the 40 patients included were females and 67.5% had diffuse cutaneous SSc. The mean age (standard deviation) was 48.5 (9.9) years and the median disease duration (interquartile range) was 8.5 (4, 13) years. There was good to excellent agreement, inter-rater ICC (dorsal fingertip range: 0.86-0.97 and volar fingertip range: 0.85-0.96), in both subgroups irrespective of operator skill.

Conclusions: LASCA is a credible instrument in patients of Black ethnicity with SSc, and across operator experience.
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July 2021

Antiphospholipid antibodies and anticoagulant therapy: capillaroscopic findings.

Arthritis Res Ther 2021 Jun 27;23(1):175. Epub 2021 Jun 27.

Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties (DiMI), University of Genova, IRCCS San Martino Polyclinic, Viale Benedetto XV, n° 6 - 16132, Genoa, Italy.

Background: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by specific vascular and obstetric manifestations and by antiphospholipid antibodies (aPL) positivity. Microvascular damage in the course of APS and "aPL carrier" patients without symptoms is poorly investigated.

Objectives: This study aims to compare nailfold videocapillaroscopy (NVC) microvascular parameters in APS patients and non-symptomatic "aPL carriers" and to investigate their possible correlations with different aPL subtypes.

Methods: NVC was performed during standard evaluations in 18 APS patients (mean age 50 ± 13.8 years), 24 "aPL carriers" without symptoms (mean age 46.4 ± 16.4 years), and 18 control patients (CTR) (mean age 74 ± 12.5 years) taking oral anticoagulants for non-immunological indications (i.e., cardiovascular accidents). All patients were investigated for the presence of dilated capillaries, giant capillaries, microhemorrhages, capillary loss, and further non-specific/specific abnormalities (i.e., branched "bushy" capillaries, sign of neoangiogenesis) by NVC. Every alteration was also classified according to a semi-quantitative score. Lupus anticoagulant, anticardiolipin antibodies, and antibeta2 glycoprotein I antibodies were tested in each patient.

Results: APS patients showed at NVC increased frequency of microhemorrhages (p = 0.039)-particularly a "comb-like" pattern (parallel hemorrhages) (p = 0.002)-than "aPL carriers". Of note, there were no significant differences concerning the isolated number of microhemorrhages between APS and the CTR group (p = 0.314), but "comb-like" hemorrhages were significantly more frequent in the APS group (p = 0.034). Not any significant correlation was found between the aPL subtypes and NVC parameters.

Conclusions: APS patients showed significantly a greater number of non-specific NVC abnormalities than "aPL carriers", particularly the "comb-like" NVC pattern. Oral anticoagulants may represent a confounding factor for isolated microhemorrhages. Not any correlation was found between aPL subtypes and NVC parameters. Further investigations are needed to better characterize the microvascular endothelium damage induced by aPL.
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http://dx.doi.org/10.1186/s13075-021-02551-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237465PMC
June 2021

Reliable detection of subtypes of nailfold capillary haemorrhages in childhood-onset systemic lupus erythematosus.

Clin Exp Rheumatol 2021 Jun 8. Epub 2021 Jun 8.

Department of Internal Medicine, Ghent University, and Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.

Objectives: In systemic lupus erythematosus (SLE), it is necessary to obtain biomarkers that predict cardiovascular complications due to premature atherosclerosis, which is related to endothelial dysfunction. Nailfold capillary abnormalities might be a biomarker for endothelial dysfunction. In adults and children with SLE, nailfold capillary haemorrhages have shown to be significantly correlated with disease activity. Recently, different subtypes of capillary haemorrhages have been described in childhood-onset SLE (cSLE). The aim of the current study was to assess the inter- and intra-rater reliability of observations of different subtypes of haemorrhages in cSLE patients.

Methods: Five raters blindly evaluated 140 capillaroscopy images from 35 cSLE-patients (diagnosed according to the 2012 SLICC criteria). The images were assessed qualitatively (present or absent) and quantitatively (total number) on four different subtypes of haemorrhages: 1) punctate extravasations, 2) perivascular haemorrhage, 3) large confluent haemorrhage and 4) non-definable. As subgroups 1) and 2) were interpreted as a continuous spectrum, a post-hoc analysis with "merged" (mean) kappa/ICC was additionally calculated as one sub-group.

Results: Qualitative assessment showed a kappa 0.65 (95% CI: 0.60-0.70) for "punctate extravasations and perivascular haemorrhages merged" and a kappa 0.78 (95% CI: 0.72-0.83) for large confluent haemorrhages. For the quantitative assessment, ICC was 0.82 (95% CI: 0.76-0.87) for the "merged groups" and ICC 0.93 (95% CI: 0.91-0.95) for large confluent haemorrhages.

Conclusions: Our study shows that different subtypes of capillary haemorrhages in cSLE-patients could be reliably reproduced by different raters. This confirms our recent observation of perivascular extravasations as a subgroup of capillary haemorrhage in cSLE that might reflect endothelial dysregulation.
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June 2021

Anti-centromere antibody levels and isotypes and the development of systemic sclerosis.

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Leiden University Medical Centre, Department of Rheumatology, Leiden, The Netherlands.

Objectives: Little is known on the disease course of very early systemic sclerosis (SSc). It is unknown whether anti-centromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. We aim to evaluate whether ACA-IgG, -IgM and -IgA levels in ACA-IgG positive patients associate with disease severity and/or progression from very early SSc to definite SSc.

Methods: ACA-IgG positive patients with very early SSc and ACA-IgG positive patients fulfilling the 2013 ACR/EULAR criteria for SSc from five different cohorts were included. A diagnosis of very early SSc was based on the presence of ACA-IgG AND Raynaud and/or puffy fingers and/or abnormal nailfold capillaroscopy but not fulfilling the 2013 ACR/EULAR criteria. Multivariable regression analyses were performed to determine the association between baseline isotype levels and progression to SSc and organ involvement.

Results: Six hundred twenty-five ACA-IgG positive patients were included of whom 138 (22%) fulfilled very early SSc criteria and 487 (78%) had definite SSc. ACA-IgG (Odds Ratio (OR) 2.5 (1.8-3.7)) and ACA-IgM (OR 1.8 (1.3 -2.3)) levels were significantly higher in definite SSc patients. Of 115 very early SSc patients with follow-up, 48 (42%) progressed to definite SSc within five years. Progression to definite SSc was associated with higher ACA-IgG levels at baseline (OR 4.3 (1.7-10.7)).

Conclusion: ACA isotype levels might serve as a biomarker to identify very early SSc patients at risk for progression to definite SSc.
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http://dx.doi.org/10.1002/art.41814DOI Listing
May 2021

HIGH FREQUENCY ULTRASONOGRAPHY: RELIABLE TOOL TO MEASURE SKIN FIBROSIS IN SSC? A systematic literature review and additional pilot study.

Rheumatology (Oxford) 2021 May 25. Epub 2021 May 25.

Department of Internal Medicine, Ghent University, Ghent, Belgium.

Objectives: To investigate the reliability of high frequency ultrasound (HFUS) in measuring skin fibrosis in systemic sclerosis (SSc).

Methods: First, a systematic review (according to PRISMA) was conducted to identify studies that documented HFUS' reliability in SSc as a primary outcome. Then, in an additional pilot study, the inter- and intra-rater reliability of two investigators performing HFUS for dermal thickness (DT) measurements in a standardised manner across all 17 areas of the modified Rodnan Skin Score was evaluated in a group of 59 SSc patients and descriptively in 44 healthy controls (HC). As an external validation, DT measurements by HFUS were performed in a separate group of 30 SSc patients by the same first and another third investigator.

Results: The systematic review retained few (4/1719 unique records) small-scale studies, with mixed study populations (combining SSc and HC). The reported data herein are suggestive of the inter-/intra-rater reliability of HFUS (ICCs ranging 0.65-0.94/0.55-0.96, respectively). Additionally, in our pilot study, inter-/intra-rater reliability was good-to-excellent in both SSc groups and HC (ICCs ranging 0.70-0.97/0.70-0.98 and 0.65-0.95/0.63-0.96, respectively).

Conclusion: The identified small-scale studies were not only combining data from SSc and HC, they were also heterogeneous in terms of technical aspects (probes and frequency), image acquisition methods ([number of] areas assessed) and definitions used for skin thickness, which prevents drawing unequivocal conclusions. Despite these limitations, our standardized pilot study corroborated the findings in literature, paving the way for the applicability of HFUS as a reliable (complementary) tool to quantify skin fibrosis in SSc.
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http://dx.doi.org/10.1093/rheumatology/keab462DOI Listing
May 2021

Representativeness of Systemic Sclerosis Patients in Interventional Randomized Trials: an analysis of the EUSTAR database.

Rheumatology (Oxford) 2021 May 14. Epub 2021 May 14.

Rheumatology Unit, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.

Objective: To estimate the extent of and the reasons for ineligibility in randomized controlled trials (RCTs) of systemic sclerosis (SSc) patients included in the EUSTAR database, and to determine the association between patient's features and generalizability of study results.

Methods: We searched Clinicaltrials.gov for all records on interventional SSc-RCTs registered from January 2013 to January 2018. Two reviewers selected studies, and information on the main trial features were retrieved. Data from 8046 patients having a visit in the EUSTAR database since 2013 were used to check patient's eligibility. The proportion of potentially eligible patients per trial, and the risk factors for ineligibility were analyzed. Complete-, worst- and best-case analyses were performed.

Results: Of the 37 RCTs included, 43% were conducted in Europe, 35% were industry-funded, and 87% investigated pharmacological treatments. Ninety-one percent of 8046 patients included could have participated in at least one RCT. In complete-case analysis, the median [range] proportion of eligible patients having the main organ complication targeted by each study was 60% [10-100] in the overall sample of trials, ranging from 50% [32-79] for trials on skin fibrosis to 90% [34-77] for those targeting Raynaud's phenomenon. Among the criteria checked, treatment- and safety-related but not demographic were the main barriers to patient's recruitment. Older age, absence of Raynaud's phenomenon, and lower mRSS were independently associated with the failure to fulfill criteria for any of the included studies.

Conclusions: Patient's representativeness in SSc-RCTs is highly variable and is driven more by treatment- and safety-related rather than demographic criteria.
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http://dx.doi.org/10.1093/rheumatology/keab437DOI Listing
May 2021

Immunopathophysiology and clinical impact of uveitis in inflammatory rheumatic diseases: An update.

Eur J Clin Invest 2021 Aug 5;51(8):e13572. Epub 2021 May 5.

Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, Italy - IRCCS Rheumatology Unit, San Martino Polyclinic, University of Genoa, Genoa, Italy.

Background: Uveitis is one of the most frequent ophthalmologic manifestations in rheumatology. Uveal inflammation can underlie a systemic inflammatory rheumatic disease (SIRD) in approximately 30% of cases with a significant burden on the quality of life since it represents a cause of blindness in up to 20% of cases in Western countries.

Methods: In this review, we provide a comprehensive overview of the pathophysiology of uveitis associated with SIRDs. According to our literature survey on the epidemiology of uveitis among SIRDs, spondyloarthritides, Behçet's disease and sarcoidosis get the major impact.

Results: In Behçet's uveitis, the key players are highly polarized Th1 and Th17 lymphocytes, natural killer T cells and γδ T cells. All contribute to a great destructive inflammatory environment with the most serious visual damage resulting from the involvement of the posterior segment of the eye. In contrast, spondyloarthritides-related uveitis derives from a complex interaction between genetic background and extra-ocular inflammatory mediators originating from enthesitis, arthritis, psoriatic lesions and microbiome pro-inflammatory alterations. In such conditions, the immune infiltration of CD4+ T cells, Th17 and natural killer cells along with pro-inflammatory cytokines, TNF-α among all, leads to intraocular inflammation. Lastly, granuloma formation represents the primary hallmark lesion in sarcoid uveitis. This suggests a profound link between the innate system that mainly recruits activated macrophages and adaptive system involving by Th1, Th17 and Th17.1 cells.

Conclusions: Awareness among rheumatologists of a potential severe ocular involvement generates new insights into targeted therapeutic approaches and personalized treatments for each patient.
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http://dx.doi.org/10.1111/eci.13572DOI Listing
August 2021

Differences sustained between diffuse and limited forms of juvenile systemic sclerosis in expanded international cohort. www.juvenile-scleroderma.com.

Arthritis Care Res (Hoboken) 2021 Mar 30. Epub 2021 Mar 30.

Hospital Universitário Clementino Fraga Filho (HUCFF), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Objectives: To evaluate the baseline clinical characteristics of juvenile systemic sclerosis (jSSc) patients in the international Juvenile SSc Inception Cohort (jSScC), compare these characteristics between the classically defined diffuse (dcjSSc) and limited cutaneous (lcjSSc) subtypes, and among those with overlap features.

Methods: A cross-sectional study was performed using baseline visit data. Demographic, organ system evaluation, treatment, and patient and physician reported outcomes were extracted and summary statistics applied. Comparisons between dcjSSc and lcSSc subtypes and patients with and without overlap features were performed using Chi-square and Mann Whitney U-tests.

Results: At data extraction 150 jSSc patients were enrolled across 42 centers, 83% were Caucasian, 80% female, dcjSSc predominated (72%), and 17% of the cohort had overlap features. Significant differences were found between dcjSSc and lcjSSc regarding the modified Rodnan Skin Score, presence of Gottron's papules, digital tip ulceration, 6 Minute walk test, composite pulmonary and cardiac involvement. All more frequent in dcSSc except for cardiac involvement. DcjSSc patients had significantly worse scores for physician rated disease activity and damage. A significantly higher occurrence of Gottron's papules, musculoskeletal involvement and composite pulmonary involvement, and significantly lower frequency of Raynaud's phenomenon, were seen in those with overlap features.

Conclusion: Results from a large international jSSc cohort demonstrate significant differences between dcjSSc and lcjSSc patients including more globally severe disease and increased frequency of ILD in dcjSSc patients, while those with lcSSc have more frequent cardiac involvement. Those with overlap features had an unexpected higher frequency of interstitial lung disease.
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http://dx.doi.org/10.1002/acr.24609DOI Listing
March 2021

A randomised, open-label trial to assess the optimal treatment strategy in early diffuse cutaneous systemic sclerosis: the UPSIDE study protocol.

BMJ Open 2021 03 18;11(3):e044483. Epub 2021 Mar 18.

Department of Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.

Introduction: Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease associated with high morbidity and mortality, especially in diffuse cutaneous SSc (dcSSc). Currently, there are several treatments available in early dcSSc that aim to change the disease course, including immunosuppressive agents and autologous haematopoietic stem cell transplantation (HSCT). HSCT has been adopted in international guidelines and is offered in current clinical care. However, optimal timing and patient selection for HSCT are still unclear. In particular, it is unclear whether HSCT should be positioned as upfront therapy or rescue treatment for patients refractory to immunosuppressive therapy. We hypothesise that upfront HSCT is superior and results in lower toxicity and lower long-term medical costs. Therefore, we propose this randomised trial aiming to determine the optimal treatment strategy for early dcSSc by comparing two strategies used in standard care: (1) upfront autologous HSCT versus (2) immunosuppressive therapy (intravenous cyclophosphamide pulse therapy followed by mycophenolate mofetil) with rescue HSCT in case of treatment failure.

Methods And Analysis: The UPSIDE (front autologous hematopoietic tem cell transplantation vs mmunosuppressive medication in early iffus cutaneous systemic sclerosis) study is a multicentre, randomised, open-label, controlled trial. In total, 120 patients with early dcSSc will be randomised. The primary outcome is event-free survival at 2 years after randomisation. Secondary outcomes include serious adverse events, functional status and health-related quality of life. We will also evaluate changes in nailfold capillaroscopy pattern, pulmonary function, cardiac MR and high-resolution CT of the chest. Follow-up visits will be scheduled 3-monthly for 2 years and annually in the following 3 years.

Ethics And Dissemination: The study was approved by the Dutch Central Committee on Research Concerning Human Subjects (NL72607.041.20). The results will be disseminated through patient associations and conventional scientific channels.

Trial Registration Numbers: NCT04464434; NL 8720.
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http://dx.doi.org/10.1136/bmjopen-2020-044483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978271PMC
March 2021

Ocular microvascular damage in autoimmune rheumatic diseases: The pathophysiological role of the immune system.

Autoimmun Rev 2021 May 13;20(5):102796. Epub 2021 Mar 13.

Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Italy - IRCCS Rheumatology Unit San Martino Polyclinic, Genoa, Italy. Electronic address:

Pathological eye involvement represents a quite common finding in a broad spectrum of autoimmune rheumatic diseases (ARDs). Ocular signs, often occur as early manifestations in ARDs, ranging from symptoms related to the mild dry eye disease to sight-threatening pathologies, linked to the immune response against retinal and choroidal vessels. Retinovascular damage driven by markedly inflammatory reactivity need a prompt diagnosis and treatment. Immune-complexes formation, complement activation and antibody-mediated endothelial damage seem to play a key role, particularly, in microvascular damage and ocular symptoms, occurring in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SS). Conversely, early alterations of retinal and choroidal vessels in the asymptomatic patient, often detectable coincidentally, might be indicators of widespread vascular injury in other connective tissue diseases. Particularly, endothelin-induced hypoperfusion and pathological peri-choroidal extracellular matrix deposition, might be responsible for the micro-architectural alterations and loss of capillaries detected in systemic sclerosis (SSc). Instead, interferon alpha-mediated microvascular rarefaction, combined with endothelial lesions caused by specific autoantibodies and immune-complexes, appear to play a significant role in retinal vasculopathy associated to inflammatory idiopathic myopathies (IIM). The immuno-pathophysiological mechanisms of ocular microcirculatory damage associated with the major ARDs will be discussed under the light of the most recent achievements.
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http://dx.doi.org/10.1016/j.autrev.2021.102796DOI Listing
May 2021

Laser speckle contrast analysis in rheumatoid arthritis: a pilot study.

Clin Exp Rheumatol 2021 Mar 9. Epub 2021 Mar 9.

Department of Internal Medicine, Ghent University, Department of Rheumatology, Ghent University Hospital, and Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, Belgium.

Objectives: Early diagnosis and treatment is paramount in rheumatoid arthritis (RA). Nowadays, there is a need for quick and non-invasive imaging modalities, for which laser speckle contrast analysis (LASCA), a technique that assesses the peripheral blood perfusion (PBP) on a microvascular level, seems to be a promising candidate. The goal of this pilot study was to examine whether the expected increased PBP in active synovitis in RA patients can be detected by LASCA.

Methods: Thirty RA patients with active synovitis in a finger joint and 44 healthy controls (HC) underwent LASCA examination. The PBP measured over the finger joints was expressed in perfusion units (PU). For the final analysis, all 30 RA patients were matched by age and gender to 30 HC. For the primary analysis the mean difference in PU between joints with active synovitis compared to matched HC, adjusted for type of joint (MCP/PIP), finger, surface and side of hand and for the matching variables (age and gender), was calculated using a multilevel linear model. For the secondary analysis this mean difference in PU was calculated on a monoarticular level.

Results: The primary analysis showed an estimated mean difference of 8.79 PU (95%CI -7.79-25.37 PU; p=0.299). For the secondary analysis on a monoarticular level, none of the estimated mean differences differed significantly.

Conclusions: In this pilot study examining the use of LASCA in RA, no significant difference in estimated mean PBP between joints with active synovitis in RA and joints without active synovitis in HC could be detected.
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March 2021

Vitamin D and Lung Outcomes in Elderly COVID-19 Patients.

Nutrients 2021 Feb 24;13(3). Epub 2021 Feb 24.

Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS San Martino Polyclinic, 16132 Genova, Italy.

Vitamin D deficiency is frequently reported in patients with SARS-CoV-2 infection. The aim of this study was to correlate the 25OH-Vitamin D serum concentrations with clinical parameters of lung involvement, in elderly patients hospitalized for SARS-CoV-2 infection. Sixty-five consecutive COVID-19 patients (mean age 76 ± 13 years) and sixty-five sex- and age-matched control subjects (CNT) were analyzed. The following clinical parameters, including comorbidities, were collected at admission: type of pulmonary involvement, respiratory parameters (PaO, SO, PaCO, PaO/FiO), laboratory parameters (including 25OH-vitamin D, D-dimer, C-reactive protein). Significantly lower vitamin D serum levels were found in COVID-19 patients than in CNT (median 7.9 vs 16.3 ng/mL, = 0.001). Interestingly, a statistically significant positive correlation was observed between vitamin D serum levels and PaO ( = 0.03), SO ( = 0.05), PaO/FiO ( = 0.02), while a statistically significant negative correlation was found between vitamin D serum levels and D-dimer ( = 0.04), C-reactive protein ( = 0.04) and percentage of O in a venturi mask ( = 0.04). A negative correlation was also observed between vitamin D serum levels and severity of radiologic pulmonary involvement, evaluated by computed tomography: in particular, vitamin D was found significantly lower in COVID-19 patients with either multiple lung consolidations ( = 0.0001) or diffuse/severe interstitial lung involvement than in those with mild involvement ( = 0.05). Finally, significantly lower vitamin D serum levels were found in the elderly COVID-19 patients who died during hospitalization, compared to those who survived (median 3.0 vs 8.4 ng/mL, = 0.046). This study confirms that 25OH-vitamin D serum deficiency is associated with more severe lung involvement, longer disease duration and risk of death, in elderly COVID-19 patients. The detection of low vitamin D levels also in younger COVID-19 patients with less comorbidities further suggests vitamin D deficiency as crucial risk factor at any age.
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http://dx.doi.org/10.3390/nu13030717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996150PMC
February 2021

Nailfold capillary abnormalities in childhood-onset systemic lupus erythematosus: a cross-sectional study compared with healthy controls.

Lupus 2021 Apr 3;30(5):818-827. Epub 2021 Mar 3.

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centers (Amsterdam UMC), University of Amsterdam, Amsterdam, the Netherlands.

Objectives: For selection of high-risk systemic lupus erythematosus (SLE) patients it is necessary to obtain indicators of disease severity that predict disease damage. As in systemic sclerosis, nailfold capillary abnormalities could be such a biomarker in SLE. The primary objective of this cross-sectional study is to describe capillary abnormalities in childhood-onset SLE (cSLE) cohort (onset < 18 years) and compare them with matched healthy controls. The secondary objective is to correlate the observed capillary abnormalities with demographical variables in both cohorts and with disease-specific variables in cSLE patients.

Methods: Healthy controls were matched for ethnic background, age and gender. Videocapillaroscopy was performed in eight fingers with 2-4 images per finger. Quantitative and qualitative assessments of nailfold capillaroscopy images were performed according to the definitions of the EULAR study group on microcirculation in Rheumatic Diseases.

Results: Both groups (n = 41 cSLE-patients and n = 41 healthy controls) were comparable for ethnic background (p = 0.317). Counted per mm, cSLE-patients showed significantly more 'giants' (p = 0.032), 'abnormal capillary shapes' (p = 0.003), 'large capillary hemorrhages' (p < 0.001) and 'pericapillary extravasations' (p < 0.001). Combined 'abnormal capillary shapes and pericapillary extravasations' (in the same finger) were detected in 78% (32/41 patients). By qualitative analysis, 'microangiopathy' was detected in 68.3% (28/41) and a 'scleroderma pattern' in 17.1% (7/41) of the cSLE-patients (without scleroderma symptoms). The difference of percentage positive anti-RNP antibodies in the group with or without a scleroderma pattern was not significant (p = 0.089). The number of 'abnormal capillary shapes per mm' was significantly correlated with treatment-naivety. The number of 'large pathological hemorrhages per mm' was significantly correlated with SLEDAI score and presence of nephritis. Compared to healthy controls, 'pericapillary extravasations' were found in significantly higher numbers per mm (p < 0.001) as well as in percentage of patients (p < 0.001).

Conclusions: Our observations confirm that giants, abnormal capillary morphology and capillary hemorrhages are also observed in cSLE, as was already known for adults with SLE. Number of capillary hemorrhages in cSLE was significantly correlated with disease activity. A high frequency and total amount of "pericapillary extravasations" was observed in cSLE patients, possibly revealing a new subtype of capillary hemorrhage that might reflect endothelial damage in these pediatric patients.
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http://dx.doi.org/10.1177/0961203321998750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020305PMC
April 2021

Assessing the impact of COVID-19 on global fossil fuel consumption and CO emissions.

Energy Econ 2021 May 15;97:105170. Epub 2021 Feb 15.

DERS, University of York, UK.

We assess the effect of the COVID-19 pandemic on global fossil fuel consumption and CO emissions over the two-year horizon 2020Q1-2021Q4. We apply a global vector autoregressive (GVAR) model, which captures complex spatial-temporal interdependencies across countries associated with the international propagation of economic impact due to the virus spread. The model makes use of a unique quarterly data set of coal, natural gas, and oil consumption, output, exchange rates and equity prices, including global fossil fuel prices for 32 major CO emitting countries spanning the period 1984Q1-2019Q4. We produce forecasts of coal, natural gas and oil consumption, conditional on GDP growth scenarios based on alternative IMF World Economic Outlook forecasts that were made before and after the outbreak. We also simulate the effect of a relative price change in fossil fuels, due to global scale carbon pricing, on consumption and output. Our results predict fossil fuel consumption and CO emissions to return to their pre-crisis levels, and even exceed them, within the two-year horizon despite the large reductions in the first quarter following the outbreak. Our forecasts anticipate more robust growth for emerging than for advanced economies. The model predicts recovery to the pre-crisis levels even if another wave of pandemic occurs within a year. Our counterfactual carbon pricing scenario indicates that an increase in coal prices is expected to have a smaller impact on GDP than on fossil fuel consumption. Thus, the COVID-19 pandemic would not provide countries with a strong reason to delay climate change mitigation efforts.
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http://dx.doi.org/10.1016/j.eneco.2021.105170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883727PMC
May 2021

Identifying unmet needs in SSc-ILD by semi-qualitative in-depth interviews.

Rheumatology (Oxford) 2021 Feb 15. Epub 2021 Feb 15.

Department of Pulmonology, University Hospitals Leuven, Leuven, Belgium.

Objectives: Interstitial lung disease is frequent in systemic sclerosis (SSc-ILD) and associates with significantly reduced quality of life. Here we aimed to analyse patient pathways, and experiences of patients and healthcare providers (HCPs) in order to identify unmet needs in the management of SSc-ILD patients.

Methods: Semi-structured qualitative interviews conducted in eight European countries looked at HCP (n=95) and patient perspective (n=47), using two sets of 70 research questions. Pre-diagnostic, diagnostic and post-diagnostic phases of the patient pathway were systematically explored.

Results: (1) In the pre-diagnostic phase several gaps were identified by HCPs and patients in all participating countries: limited disease knowledge among primary care physicians and specialists, lack of accurate patient information, delayed and/or inappropriate referral. (2) The diagnostic phase is in most countries coordinated by rheumatologists also being the main point of care. Depending on the local health system, organisation of multidisciplinary collaboration varies. HCPs issued lack of national guidelines, while patients stated difficulties obtaining disease-related information. (3) In the post-diagnostic phase, HCPs and patients indicated lack of curative treatment, specialized nurses, paramedical and psychological support. Patients and caregivers additionally expressed the need for clear information on SSc-ILD.

Conclusion: Lack of disease specific knowledge, gaps in national healthcare systems and insufficient information and support for patients and caregivers were identified as unmet needs to ensure timely diagnosis, provide better patient management and to improve quality of life in SSc ILD patients.
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http://dx.doi.org/10.1093/rheumatology/keab154DOI Listing
February 2021

The clinical phenotype of Systemic Sclerosis patients with anti-PM/Scl antibodies: results from the EUSTAR cohort.

Rheumatology (Oxford) 2021 Feb 12. Epub 2021 Feb 12.

Division of Rheumatology, Hospital IRCCS Policlinico S. Matteo Foundation of Pavia, University of Pavia, Pavia, Italy.

Objective: To evaluate clinical associations of anti-PM/Scl antibodies in patients with Systemic Sclerosis (SSc) in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (SRC), malignancies, and functional outcome of interstitial lung disease (ILD).

Methods: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared to 7,202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc (85 from the EUSTAR registry), and compared to 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset.

Results: Patients with isolated anti-PM/Scl positivity, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of dermatomyositis, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls.In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed.

Conclusion: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous dermatomyositis, calcinosis, and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.
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http://dx.doi.org/10.1093/rheumatology/keab152DOI Listing
February 2021

Durometry in SSc: The hard facts. A systematic literature review and additional pilot study.

Rheumatology (Oxford) 2021 05;60(5):2099-2108

Department of Internal Medicine, Ghent University.

Objectives: To investigate the reliability of durometry in systemic sclerosis (SSc), by means of a systematic review and additional pilot study.

Methods: Literature was systematically reviewed according to the PRISMA guidelines to identify all original studies assessing the reliability of durometry in SSc. Additionally, in the pilot study, intra-rater reliability was evaluated in a first cohort of 74 SSc patients (61 female, 13 LSSc/53 LcSSc/8 DcSSc). In a second separate set of 30 SSc patients (21 female, 4 LSSc/20 LcSSc/6 DcSSc), intra- and inter-rater reliability were evaluated.

Results: Only two unique records identified through the systematic review were qualified to generate conclusions. Regarding intra-rater reliability, Kissin reported excellent intra-class correlation coefficient values (ICC, 0.86-0.94) for measurements at nine skin sites in two DcSSc patients. Merkel and Kissin described, both in five DcSSc patients, good to excellent inter-rater reliability (ICC, 0.82-0.96 and 0.61-0.85) for measurements at respectively, six and nine skin sites. In our pilot study, ICC for intra-rater reliability at 17 standardized skin sites were excellent in both cohorts, ranging 0.93-0.99 and 0.78-0.98, respectively. ICC for inter-rater reliability at 17 standardized skin sites were good to excellent 0.63-0.93, except for the feet (0.48 and 0.52).

Conclusion: The preliminary findings in the literature are supported by our pilot study in which we have attested the reliability of durometry in SSc patients. However, prior to including durometry as an (additional) outcome measure in SSc clinical trials, its validation status in the assessment of skin fibrosis needs to be completely attested.
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http://dx.doi.org/10.1093/rheumatology/keab028DOI Listing
May 2021

The impact of COVID-19 on rare and complex connective tissue diseases: the experience of ERN ReCONNET.

Nat Rev Rheumatol 2021 03 6;17(3):177-184. Epub 2021 Jan 6.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies.
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http://dx.doi.org/10.1038/s41584-020-00565-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786339PMC
March 2021

Evidences for a protective role of vitamin D in COVID-19.

RMD Open 2020 12;6(3)

Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.

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http://dx.doi.org/10.1136/rmdopen-2020-001454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771215PMC
December 2020

A Distal Radius Nonunion Treated with A Dorsal Spanning Distraction Plate: A Case Report.

S D Med 2020 Sep;73(9):394-398

Sanford Orthopedics and Sports Medicine, Sioux Falls, South Dakota.

Distal radius fractures are one of the most common orthopedic injuries, particularly in the elderly population. Distal radius nonunions are rare and are usually associated with a patient's underlying health conditions. We present a patient who developed a distal radius nonunion following treatment of an open wrist fracture with an external fixation frame. This nonunion was successfully treated with a dorsal spanning distraction plate. The etiology of distal radius nonunions and treatment options are reviewed.
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September 2020

Peripheral blood perfusion in patients with systemic lupus erythematosus and in primary Raynaud's phenomenon.

Eur J Rheumatol 2021 Jan 11;8(1):7-11. Epub 2020 Nov 11.

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, San Martino Polyclinic Hospital, University of Genova, Genoa, Italy.

Objective: This study aims to evaluate blood perfusion (BP) in various cutaneous regions of the hands and face in patients with systemic lupus erythematosus (SLE) and primary Raynaud's phenomenon (PRP) and healthy subjects (HS).

Methods: A total of 20 patients with SLE, 20 patients with PRP, and 20 HS were enrolled. BP was detected by laser speckle contrast analysis in different regions of the hand and at the facial level. The absolute nailfold capillary number (CN) was assessed by nailfold videocapillaroscopy.

Results: Patients with SLE and PRP had significantly lower BP levels than those of HS in 3 hand areas (fingertip, palm, and periungual; p<0.01). However, the SLE, PRP, and HS groups had comparable BP values at the hand dorsum and face. The BP and CN values revealed a positive correlation in the periungual, fingertip, and palm of hands (p<0.01), only in patients with SLE.

Conclusion: Our data demonstrated a correlation between functional and morphological microvascular impairment in patients with SLE.
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http://dx.doi.org/10.5152/eurjrheum.2020.20027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861644PMC
January 2021

Under detection of interstitial lung disease in juvenile systemic sclerosis (jSSc).

Arthritis Care Res (Hoboken) 2020 Nov 3. Epub 2020 Nov 3.

Meyer Children's Hospital, Florence, Italy.

Objectives: Utilizing data obtained from a prospective international juvenile systemic sclerosis cohort (jSScC) to determine if pulmonary screening with forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) is sufficient to assess the presence of interstitial lung disease (ILD) in comparison to high resolution computed tomography (HRCT) in jSSc.

Methods: The jSScC cohort database was queried for patients enrolled from January 2008 to January 2020 with recorded pulmonary function tests (PFT) parameters and HRCT to determine the discriminatory properties of PFTs parameters, FVC and DLCO, in detecting ILD.

Results: Eighty-six jSSc patients had both CT imaging and FVC values for direct comparison. Using findings on HRCT as the standard measure of ILD presence, the sensitivity of FVC in detecting ILD in jSSc was only 40%, the specificity was 77%, and AUC was 0.58. Fifty-eight jSSc patients had both CT imaging and DLCO values for comparison. The sensitivity of DLCO in detecting ILD was 76%, the specificity was 70%, and AUC was 0.73.

Conclusion: The performance of PFTs in jSSc to detect underlying ILD was quite limited. Specifically, the FVC, which is one of the main clinical parameters in adult SSc to detect and monitor ILD, would miss approximately 60% of children that had ILD changes on their accompanying HRCT. The DLCO was more sensitive in detecting potential abnormalities in HRCT, but with less specificity than the FVC. These results support the use of HRCT in tandem with PFTs for the screening of ILD in jSSc.
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http://dx.doi.org/10.1002/acr.24499DOI Listing
November 2020

Epigenetics, pregnancy and autoimmune rheumatic diseases.

Autoimmun Rev 2020 Dec 22;19(12):102685. Epub 2020 Oct 22.

Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS San Martino Polyclinic Hospital, Genova, Italy. Electronic address:

Autoimmune rheumatic diseases (ARDs) are chronic conditions with a striking female predominance, frequently affecting women of childbearing age. Sex hormones and gender dimorphism of immune response are major determinants in the multifactorial pathogenesis of ARDs, with significant implications throughout reproductive life. Particularly, pregnancy represents a challenging condition in the context of autoimmunity, baring profound hormonal and immunologic changes, which are responsible for the bi-directional interaction between ARDs outcome and pregnancy course. In the latest years epigenetics has proven to be an important player in ARDs pathogenesis, finely modulating major immune functions and variably tuning the significant gender effects in autoimmunity. Additionally, epigenetics is a recognised influencer of the physiological dynamic modifications occurring during pregnancy. Still, there is currently little evidence on the pregnancy-related epigenetic modulation of immune response in ARDs patients. This review aims to overview the current knowledge of the role of epigenetics in the context of autoimmunity, as well as during physiologic and pathologic pregnancy, discussing under-regarded aspects in the interplay between ARDs and pregnancy pathology. The outline of a new ongoing European project will be presented.
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http://dx.doi.org/10.1016/j.autrev.2020.102685DOI Listing
December 2020

Nailfold capillaroscopy in Sjögren's syndrome: a systematic literature review and standardised interpretation.

Clin Exp Rheumatol 2020 Jul-Aug;38 Suppl 126(4):150-157. Epub 2020 Sep 21.

Department of Rheumatology, Ghent University Hospital; Department of Internal Medicine, Ghent University, and Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Centre (IRC), Ghent, Belgium.

Objectives: To identify the role of nailfold capillaroscopy (NC) in Sjögren's syndrome (SS).

Methods: The literature was systematically reviewed in three databases. All published original studies which assess patients with SS by NC were revised. A quality assessment was applied to all studies based on population description, presence of a control group, presence of instrumental specifications and/or standardly applied NC methodology, presence of clear descriptions of capillaroscopic characteristics and based on the used statistical analysis. The capillaroscopic findings per study were described in a EULAR consented standardised way. Significant associations of capillaroscopic characteristics in SS patients with clinical and laboratory variables were summarised.

Results: The search resulted in 869 hits. Based on title and abstract screening 29 original studies were identified and of these, 14 full texts described an assessment by NC in SS. Seven studies were retained after performing a critical quality assessment. One study compared NC in SS with healthy controls and attested a lower capillary density in SS. Concerning clinical associations, capillary density was associated with Raynaud's phenomenon in two studies and with interstitial lung disease or systemic manifestations in one study each. No association between serologic features (anti-nuclear antibodies, anti-SSA, anti-SSB and anti-RF) and NC characteristics were found.

Conclusions: A small number of studies have investigated the role of NC in SS. More studies, including prospective follow up studies with standard NC evaluation in SS are needed.
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October 2020

Reporting items for capillaroscopy in clinical research on musculoskeletal diseases: a systematic review and international Delphi consensus.

Rheumatology (Oxford) 2021 03;60(3):1410-1418

Department of Internal Medicine, Ghent University, Ghent, Belgium.

Objectives: The level of detail included when describing nailfold videocapillaroscopy (NVC) methods varies among research studies, making interpretation and comparison of results challenging. The overarching objective of the present study was to seek consensus on the reporting standards in NVC methodology for clinical research in rheumatic diseases and to propose a pragmatic reporting checklist.

Methods: Based on the items derived from a systematic review focused on this topic, a three-step web-based Delphi consensus on minimum reporting standards in NVC was performed among members of the European League against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases and the Scleroderma Clinical Trials Consortium.

Results: A total of 319 articles were selected by the systematic review, and 46 items were proposed in the Delphi process. This Delphi exercise was completed by 80 participants from 31 countries, including Australia and countries within Asia, Europe, North America and South America. Agreement was reached on items covering three main areas: patient preparation before NVC (15 items), device description (5 items) and examination details (13 items).

Conclusion: Based on the available evidence, the description of NVC methods was highly heterogeneous in the identified studies and differed markedly on several items. A reporting checklist of 33 items, based on practical suggestions made (using a Delphi process) by international participants, has been developed to provide guidance to improve and standardize the NVC methodology to be applied in future clinical research studies.
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http://dx.doi.org/10.1093/rheumatology/keaa457DOI Listing
March 2021

Clinical practice guidelines adherence, knowledge and awareness in rare and complex connective tissue diseases across Europe: results from the first ERN ReCONNET survey.

RMD Open 2020 08;6(2)

Rheumatology Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.

Introduction: The European Reference Network (ERN) ReCONNET is the ERN aimed at improving the management of rare and complex connective tissue and musculoskeletal diseases (rCTDs) across the European Union (EU). In the mission of ERN ReCONNET, clinical practice guidelines (CPGs) play a crucial role, representing a valid tool towards the harmonisation of the management of rCTDs while improving effectiveness and quality of care delivered to patients.

Methods: ERN ReCONNET developed two surveys to map the adherence to rCTDs CPGs among healthcare providers and to assess the knowledge and awareness of CPGs for their diseases among patients, family members and caregivers.

Results: The results of the surveys highlighted that healthcare professionals find it useful to apply CPGs in clinical practice (93%), while 62% of them experience difficulties and barriers in the application in their centres. Healthcare professionals also highlighted the need to develop CPGs for all rCTDs and to implement the use of the existing CPGs in clinical practice. On the other hand, patients, families and caregivers are relatively aware of the purpose of CPGs (51%) and 62% of them were aware of the existence of CPGs for their disease. Patient-friendly versions of CPGs and patients' lifestyle guidelines should be systematically developed contributing to the empowerment of patients in the disease management.

Conclusion: ERN ReCONNET is addressing the main issues identified in the results of the survey, promoting practical actions for the local adaptation of CPGs across Europe, improving their routine clinical use and increasing the awareness on CPGs among rCTDs patients, family members and caregivers.
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http://dx.doi.org/10.1136/rmdopen-2020-001344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507993PMC
August 2020

Consensus-based evaluation of dermatoscopy versus nailfold videocapillaroscopy in Raynaud's phenomenon linking USA and Europe: a European League against Rheumatism study group on microcirculation in rheumatic diseases project.

Clin Exp Rheumatol 2020 May-Jun;38 Suppl 125(3):132-136. Epub 2020 Aug 26.

Department of Rheumatology, Ghent University Hospital, and Department of Internal Medicine, Ghent University, Belgium.

Objectives: Nailfold videocapillaroscopy (NVC) is the current gold standard for detection and quantification of capillary abnormalities in Raynaud's phenomenon (RP). The objective of this study is to evaluate the role of dermatoscopy as a further screening tool in RP.

Methods: Nailfold capillaries of RP patients were examined by a hand-held non-contact polarised dermatoscope connected to the digital camera (D1) and connected to an iPad (D2). Both dermatoscopic images were marked with an arrowhead. NVC examination was evaluated at the arrowhead. Single blinded reader performed all examinations. NVC was graded as per standard of European League against Rheumatism (EULAR) study group on microcirculation in rheumatic diseases. Consensus evaluation of dermatoscopy characteristics/grade was determined and each dermatoscopic image was given a final impression of 'normal', 'non-specific' or 'scleroderma' pattern. The final interpretation by both techniques was compared after completion of the blinded reading.

Results: Classification of 100 consecutive dermatoscopic images resulted in 37 (wide view) 'non-interpretable', 2 'normal', 48 'non-specific' and 13 'scleroderma' pattern with D1; 23 'non-interpretable', 4 'normal', 52 'non-specific' and 21 'scleroderma' pattern by the experts with D2; 0 non-interpretable, 4 normal, 13 non-specific and 83 'scleroderma' pattern with NVC.

Conclusions: Overall, 50% of dermatoscopic images were classified as non-specific and 30% were classified as non-interpretable in RP patients. However, all images classified by dermatoscopy as "normal" or as overt "scleroderma" pattern were confirmed by concomitant NVC analysis. These findings demonstrate tenuous promise for dermatoscopy as a tool for the initial screening of nailfold capillaries in RP. Further regular work up with NVC is needed to further clarify non-interpretable and non-specific findings possibly related to non-scleroderma patterns.
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September 2020

Apremilast interferes with the TGFβ1-induced transition of human skin fibroblasts into profibrotic myofibroblasts: in vitro study.

Rheumatology (Oxford) 2020 12;59(12):3927-3938

Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS Polyclinic San Martino Hospital, Genoa.

Objectives: Fibroblast-to-myofibroblast transition and extracellular matrix overproduction represent progressive events in chronic inflammatory and fibrotic diseases, in which TGFβ1 is one of the key mediators. Phosphodiesterase 4 (PDE4) acts as a proinflammatory enzyme through the degradation of cyclic adenosine monophosphate and it is overexpressed in skin fibroblasts. The study investigated how apremilast (a PDE4 inhibitor) interferes with the intracellular signalling pathways responsible for the TGFβ1-induced fibroblast-to-myofibroblast transition and profibrotic extracellular matrix protein synthesis.

Methods: Cultured human skin fibroblasts were stimulated with TGFβ1 (10 ng/ml) alone or combined with apremilast (1 and 10 μM) for 4, 16 and 24 h. Other aliquots of the same cells were previously stimulated with TGFβ1 and then treated with apremilast (1 and 10 μM) for 4, 16 and 24 h, always under stimulation with TGFβ1. Gene and protein expression of αSMA, type I collagen (COL1) and fibronectin were evaluated, together with the activation of small mothers against decapentaplegic 2 and 3 (Smad2/3) and extracellular signal-regulated kinase (Erk1/2) proteins.

Results: Apremilast reduced the TGFβ1-induced increase in αSMA, COL1 and fibronectin gene expression at 4 and 16 h, and protein synthesis at 24 h of treatment in cultured fibroblasts, even for cells already differentiated into myofibroblasts by way of a previous stimulation with TGFβ1. Apremilast inhibited the TGFβ1-induced Smad2/3 and Erk1/2 phosphorylation at 15 and 30 min.

Conclusion: Apremilast seems to inhibit in vitro the fibroblast-to-myofibroblast transition and the profibrotic activity induced by TGFβ1 in cultured human skin fibroblasts by downregulating Smad2/3 and Erk1/2 intracellular signalling pathways.
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http://dx.doi.org/10.1093/rheumatology/keaa249DOI Listing
December 2020